Pharmaceutics
·
2024
·Vol. 16
·期 12
·1596
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IF 4.9
Xiaoqiang Zhu,Weimin Kong,Zehua Wang,Xiaodong Liu,Li Liu
Background/Objectives:SPT-07A, a D-borneol, is currently being developed in China for the treatment of ischemic stroke. We aimed to create a whole-body physiologically-based pharmacokinetic (PBPK) model to predict the pharmacokinetics of SPT-07A in rats, dogs, and humans.Methods:The in vitro metabolism of SPT-07A was studied using hepatic, renal, and intestinal microsomes. The pharmacokinetics of SPT-07A in rats were simulated using the developed PBPK model and in vitro data. Following validation using pharmacokinetic data in rats, the developed PBPK model was scaled up to dogs and humans.Results:Data from hepatic microsomes revealed that SPT-07A was primarily metabolized by UDP-glucuronosyltransferase (UGTs). Glucuronidation of SPT-07A also occurred in the kidney and intestine. The in vitro to in vivo extrapolation analysis showed that hepatic clearance of SPT-07A in rats, dogs, and humans accounted for 62.2%, 87.3%, and 76.5% of the total clearance, respectively. The renal clearance of SPT-07A in rats, dogs, and humans accounted for 32.6%, 12.7%, and 23.1% of the total clearance, respectively. Almost all of the observed concentrations of SPT-07A following single or multi-dose to rats, dogs, and humans were within the 5th–95th percentiles of simulations from 100 virtual subjects. Sensitivity analysis showed that hepatic metabolic velocity, renal metabolic velocity, and hepatic blood flow remarkably affected the exposure to SPT-07A in humans. Dedrick plots were also used to predict the pharmacokinetics of SPT-07A in humans. Prediction accuracy using the PBPK model is superior to that of Dedrick plots.Conclusions:We elucidate UGT-mediated SPT-07A metabolism in the liver, kidney, and intestine of rats, dogs, and humans. The pharmacokinetics of SPT-07A were successfully simulated using the developed PBPK model.
研究领域:
药理学
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生物医学工程
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药物代谢研究
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产品关联
DOI
PubMed
高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2022
·Vol. 130
·期 5
·592-605
·
IF 3.688
Zhiping Jin,Qingfeng He,Xiao Zhu,Mingshe Zhu,Yike Wang,Xin-an Wu,Qianzhou Lv,Xiaoqiang Xiang
Anlotinib is a small molecule of novel tyrosine kinase inhibitor initially approved to treat non-small cell lung cancer in China. Drug–drug interaction (DDI) is an extrinsic factor important for the appropriate use of anlotinib in clinical practice. In vitro experiments demonstrated that anlotinib is a substrate of cytochrome P450 (CYP) enzymes and moderate inhibitor of several common ones; however, no clinical DDI studies have been performed to investigate inhibitory effects of anlotinib on these CYP enzymes. Thus, its drug label recommends avoiding co-administration with substrates of these enzymes, which have narrow therapeutic windows. In this study, we performed a CYP450 inhibition study, followed by gathering in vitro and clinical pharmacokinetic data to build the first physiologically based pharmacokinetic (PBPK) model of anlotinib. The verified model was subsequently used to predict the DDI mediated by anlotinib. As a result, the marginal plasma exposure changes of typical CYP3A and CYP2C9 substrates were less than the bioequivalence threshold, indicating that anlotinib has a very low potential of causing clinically meaningful DDI through the inhibition of several major CYP enzymes. According to the FDA's latest guideline on DDI, the established model with the simulation results may support the revision of anlotinib labelling without further clinical studies, lifting unnecessary restrictions on anlotinib regimens.
研究领域:
药理学
·
临床药学
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DOI
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Lina Zhong,Longjie Li,Qingfeng He,Xiao Zhu,Ping Xiang,Xiaoqiang Xiang,Hui Yan
U-47700, a synthetic μ-opioid receptor agonist and emerging new psychoactive substance, poses critical public health risks due to its high abuse liability and fatal overdose potential. Ethical barriers prohibit clinical pharmacokinetic studies of such controlled substances, necessitating alternative approaches. Here, we developed the first physiologically based pharmacokinetic (PBPK) model for U-47700 by integrating in vitro experiments—including Caco-2 permeability, tissue-plasma partitioning, plasma protein binding, and human liver microsomal clearance. The rat PBPK model accurately predicted plasma concentration-time profiles across doses, and the metabolite's PBPK model was further established and validated to describe the kinetics of N -desmethyl-U-47700 and N , N -didesmethyl-U-47700. Human extrapolation via IVIVE ( in vitro-in vivo extrapolation) and allometric scaling revealed rapid systemic clearance (0.944–1.371 L/h/kg). For illicit drugs like U-47700, where clinical trials are unfeasible, this PBPK framework bridges computational modeling, preclinical insights, and real-world evidence, offering a critical tool to decode pharmacokinetic curves, estimate administration timelines from postmortem samples, and assess polydrug interaction risks. By enabling mechanistic insights into synthetic opioid toxicity, this work informs overdose prevention strategies and mitigates the societal impact of high-risk designer drugs.
研究领域:
毒理学
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药理学
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计算生物学
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2023
·Vol. 51
·期 11
·1515-1526
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IF 3.9
Xiaowen Wang,Yiqun Yu,Hongrui Liu,Fengjiao Bu,Chunying Shen,Qingfeng He,Xiao Zhu,Pin Jiang,Bing Han,Xiaoqiang Xiang
Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non–small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug–drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib. Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro, in silico, and in vivo parameters, verified using clinical data, and applied to predict the clinical DDI mediated by ensartinib. The in vitro incubation experiments suggested that ensartinib exhibited strong time-dependent inhibition. Simulation results from the PBPK model indicated a significant increase in the exposure of CYP3A substrates in the presence of ensartinib, with the maximal plasma concentration and area under the plasma concentration-time curve increasing up to 12-fold and 29-fold for sensitive substrates. Based on these findings, it is evident that co-administration of ensartinib and CYP3A substrates requires careful regulatory consideration.
研究领域:
药理学
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临床药学
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生物医学工程
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DOI
PubMed
高影响因子
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